{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T18:42:16Z","timestamp":1793472136119,"version":"4.5.0"},"reference-count":98,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T00:00:00Z","timestamp":1616371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The RAG1 and RAG2 proteins initiate the process of V(D)J recombination and therefore play an essential role in adaptive immunity. While null mutations in the <jats:italic>RAG<\/jats:italic> genes cause severe combined immune deficiency with lack of T and B cells (T<jats:sup>\u2212<\/jats:sup>B<jats:sup>\u2212<\/jats:sup> SCID) and susceptibility to life\u2010threatening, early\u2010onset infections, studies in humans and mice have demonstrated that hypomorphic <jats:italic>RAG<\/jats:italic> mutations are associated with defects of central and peripheral tolerance resulting in immune dysregulation. In this review, we provide an overview of the extended spectrum of RAG deficiencies and their associated clinical and immunological phenotypes in humans. We discuss recent advances in the mechanisms that control RAG expression and function, the effects of perturbed RAG activity on lymphoid development and immune homeostasis, and propose novel approaches to correct this group of disorders.<\/jats:p>","DOI":"10.1002\/eji.202048880","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T04:20:46Z","timestamp":1615177246000},"page":"1028-1038","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches"],"prefix":"10.1002","volume":"51","author":[{"given":"Marita","family":"Bosticardo","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology National Institute of Allergy and Infectious Diseases National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pala","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology National Institute of Allergy and Infectious Diseases National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi D.","family":"Notarangelo","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology National Institute of Allergy and Infectious Diseases National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90760-5"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2360047"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.28"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.10.055"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.03.008"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0216137"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90030-G"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90029-C"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5284.97"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12713"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2009.03.008"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.179.4.1355"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1831564"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90453-J"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1439838"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay3224"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(95)90131-0"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.036"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5430.1080"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1053"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20142207"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.22.12713"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(03)00181-X"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1612"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110645"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301675"},{"key":"e_1_2_6_28_1","first-page":"38","article-title":"Corrected and republished from: BCL11A is a critical component of a transcriptional network that activates RAG expression and V(D)J recombination","author":"Lee B. S.","year":"2018","journal-title":"Mol Cell Biol"},{"key":"e_1_2_6_29_1","first-page":"37","article-title":"Dual mechanism of Rag gene repression by c\u2010Myb during pre\u2010B cell proliferation","author":"Timblin G. A.","year":"2017","journal-title":"Mol Cell Biol"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1225"},{"key":"e_1_2_6_31_1","doi-asserted-by":"crossref","first-page":"5071","DOI":"10.4049\/jimmunol.158.11.5071","article-title":"Regulation of the RAG\u20101 promoter by the NF\u2010Y transcription factor","volume":"158","author":"Brown S. T.","year":"1997","journal-title":"J Immunol"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.7.4567"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20181402"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.7150\/jca.33989"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-018-0537-4"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.17056.1"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-019-00717-1"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-01-476432"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-03-840702"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.09.044"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25221"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25178"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.6.1847"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.08.001"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81448-8"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.10.007"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.04.027"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00900"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.11.028"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.08.027"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa073966"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2019.02.038"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI91162"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-329052"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2019.00122"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-014-0121-5"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.04.042"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2010.02.005"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1097\/DAD.0000000000001492"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.574738"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1097\/ACI.0000000000000694"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.06.030"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2019.03.022"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.05.028"},{"key":"e_1_2_6_65_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400915"},{"key":"e_1_2_6_66_1","doi-asserted-by":"publisher","DOI":"10.5625\/lar.2018.34.4.166"},{"key":"e_1_2_6_67_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30513"},{"key":"e_1_2_6_68_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-12-820985"},{"key":"e_1_2_6_69_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30928"},{"key":"e_1_2_6_70_1","first-page":"259","article-title":"Rag defects and thymic stroma: lessons from animal models","volume":"5","author":"Marrella V.","year":"2014","journal-title":"Front Immunol"},{"key":"e_1_2_6_71_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-01-406827"},{"key":"e_1_2_6_72_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091928"},{"key":"e_1_2_6_73_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151116"},{"key":"e_1_2_6_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.04.005"},{"key":"e_1_2_6_75_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-07-165167"},{"key":"e_1_2_6_76_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2011.00015"},{"key":"e_1_2_6_77_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091927"},{"key":"e_1_2_6_78_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3491"},{"key":"e_1_2_6_79_1","first-page":"2145","article-title":"The immunophenotypic and immunogenotypic B\u2010cell differentiation arrest in bone marrow of RAG\u2010deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins","volume":"100","author":"Noordzij J. G.","year":"2002","journal-title":"Blood"},{"key":"e_1_2_6_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.11.003"},{"key":"e_1_2_6_81_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-10-676304"},{"key":"e_1_2_6_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.11.018"},{"key":"e_1_2_6_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2019.12.010"},{"key":"e_1_2_6_84_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4237"},{"key":"e_1_2_6_85_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020001730"},{"key":"e_1_2_6_86_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020001736"},{"key":"e_1_2_6_87_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-04-1293"},{"key":"e_1_2_6_88_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200523087"},{"key":"e_1_2_6_89_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-03-211029"},{"key":"e_1_2_6_90_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-02-267583"},{"key":"e_1_2_6_91_1","first-page":"11","article-title":"Lymphocyte\u2010driven regional immunopathology in pneumonitis caused by impaired central immune tolerance","author":"Ferre E. M. N.","year":"2019","journal-title":"Sci Transl Med"},{"key":"e_1_2_6_92_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2019.00434"},{"key":"e_1_2_6_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.04.033"},{"key":"e_1_2_6_94_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-05-2032"},{"key":"e_1_2_6_95_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2011.106"},{"key":"e_1_2_6_96_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.10.009"},{"key":"e_1_2_6_97_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2012.110"},{"key":"e_1_2_6_98_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.11.015"},{"key":"e_1_2_6_99_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-021-00989-6"}],"container-title":["European Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/eji.202048880","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/eji.202048880","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/eji.202048880","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T07:06:14Z","timestamp":1693206374000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/eji.202048880"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,22]]},"references-count":98,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,5]]}},"alternative-id":["10.1002\/eji.202048880"],"URL":"https:\/\/doi.org\/10.1002\/eji.202048880","archive":["Portico"],"relation":{},"ISSN":["0014-2980","1521-4141"],"issn-type":[{"value":"0014-2980","type":"print"},{"value":"1521-4141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,22]]},"assertion":[{"value":"2021-01-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}